2024-03-28T09:08:26Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/509822023-07-27T07:22:23Zhdl_2115_20044hdl_2115_124Transport of estrone 3-sulfate mediated by organic anion transporter OATP4C1: estrone 3-sulfate binds to the different recognition site for digoxin in OATP4C1.Yamaguchi, HiroakiSugie, MisaOkada, MasahiroMikkaichi, TsuyoshiToyohara, TakafumiAbe, TakaakiGoto, JunichiHishinuma, TakanoriShimada, MikiMano, NariyasuOATP4C1estrone 3-sulfatedigoxinmutual inhibitionrecognition site499AnimalsBinding, CompetitiveBiological Transport/drug effectsCell LineChenodeoxycholic Acid/metabolismCyclosporine/metabolismDigoxin/metabolismDogsEpithelial CellsEstrone/analogs & derivativesEstrone/metabolismHumansKidney/cytologyKidney/metabolismOrganic Anion Transporters/antagonists & inhibitorsOrganic Anion Transporters/metabolismOuabain/metabolismPharmacokineticsSulfobromophthalein/metabolismTriiodothyronine/metabolismHuman organic anion transporter OATP4C1 is a member of the OATP family predominantly expressed in the kidney, and contributes to the renal secretion of digoxin. However, little is known about the characteristics of OATP4C1-madiated transport. We examined the transport of estrone 3-sulfate, which is known as a substrate for other OATPs, by OATP4C1-expressing cells. Estrone 3-sulfate was efficiently transported by OATP4C1. The Michaelis-Menten constant for estrone 3-sulfate uptake by OATP4C1 was 26.6+/-4.9 microM. Transport of estrone 3-sulfate was significantly inhibited by triiodothyronine, chenodeoxycholic acid, bromosulfophtalein, and cyclosporine, whereas known substrates of OATP4C1, digoxin and ouabain, did not change OATP4C1-mediated transport. We further examined the mutual inhibition study between estrone 3-sulfate and digoxin. Digoxin partially inhibited the estrone 3-sulfate transport, and estrone 3-sulfate did not significantly inhibit digoxin transport. The estimated IC(50) value of digoxin for OATP4C1-mediated estrone 3-sulfate transport was 119 microM. This value is not comparable with the Michaelis-Menten constant for digoxin uptake by OATP4C1 (7.8 microM) reported by Mikkaichi et al.(1)) In conclusion, we found that estrone 3-sulfate is a novel substrate for OATP4C1. Moreover, our results indicate that estrone 3-sulfate does not bind to the recognition site for digoxin in OATP4C1.Japanese Society for the Study of XenobioticsJournal Articleapplication/pdfhttp://hdl.handle.net/2115/50982https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/50982/1/Drug_Metab_Pharmacokinet_25_3_314-317_2010..pdf1880-0920Drug metabolism and pharmacokinetics2533143172010enginfo:pmid/20610891info:doi/10.2133/dmpk.25.314publisher